Articles about diseases

Posts Tagged ‘history’

The drug, Keytruda (pembrolizumab), was tested on more than 600 patients who had melanoma that had spread throughout their bodies. Because so many of the patients in the early testing showed significant long-lasting responses, the study was continued and the FDA granted the drug “breakthrough therapy” status, allowing it to be fast-tracked for approval.

The largest Phase 1 study in the history of oncology, the research was conducted at UCLA and 11 other sites in the U.S., Europe and Australia.

Keytruda, formerly known as MK-3475, is an antibody that targets a protein called PD-1 that is expressed by immune cells. The protein puts the immune system’s brakes on, keeping its T cells from recognizing and attacking cancer cells, said Dr. Antoni Ribas, the study’s principal investigator and a professor of medicine in the division of hematology-oncology at the David Geffen School of Medicine at UCLA.

For many years, when using immunotherapy to fight cancer, doctors’ strategy has been to bolster the immune system so it could kill the cancer cells. But the approach had limited success because PD-1 prevented the immune system from becoming active enough to attack the cancer.

Keytruda, in effect, cuts the brake lines, freeing up the immune system to attack the cancer.

“This drug is a game changer, a very significant advance in the treatment of melanoma,” said Ribas, who also is a researcher at UCLA’s Jonsson Comprehensive Cancer Center. “For patients who have not responded to prior therapies, this drug now provides a very real chance to shrink their tumors and the hope of a lasting response to treatment.”

Judith Gasson, senior associate dean for research at the David Geffen School of Medicine at UCLA and director of the Jonsson Cancer Center, said researchers have long hoped to develop an effective and lasting immunotherapy to fight cancer.

“We have long believed that harnessing the power of our own immune systems would dramatically alter cancer treatment,” she said. “Based upon work conducted over the past two decades, we are beginning to see the clinical benefits of this research in some of the most challenging cancers.”

Generally, about 1 in 10 patients responded to previous immunotherapy drugs. Some of those who responded, however, exhibited long-lived benefits, which sustained scientists’ interest in the method as an effective mechanism to fight cancer.

The response and duration rates for Keytruda were much greater than for previous drugs, Ribas said. In the new study, 72 percent of patients responded to the drug, meaning that their tumors shrank to some degree. Overall, 34 percent of patients showed an objective response, meaning that their tumors shrank by more than 30 percent, and did not re-grow.

Ribas said Keytruda has the potential to be used to treat other cancers that the immune system can recognize, including cancers of the lung, bladder, head and neck.

Survivors’ stories Kathy Thomas, 59, of Torrance, California, was diagnosed in September 2011 with melanoma that had spread to her liver and was invading her left breast. She underwent several therapies that did not work, and she was weakening fast.

“I lost weight. I threw up nearly every day,” Thomas said. “My hair was thinning. I just had no strength at all. I was so sick I had to use a wheelchair.”

Thomas met with Ribas in 2012 but was skeptical about enrolling in a trial to test an experimental therapy. She soon overcame her hesitation.

Since enrolling in the study, Thomas’ tumors have shrunk. She regained her strength and her appetite. She’s out of her wheelchair and walking normally again. She said she has experienced no side effects from the therapy, and she travels monthly to San Francisco to visit her grandson.

Tom Stutz, 74, of Sherman Oaks, California, was diagnosed in June 2011 with melanoma that had spread to his lung, liver and other parts of his body. He didn’t see how he could survive, but he decided to enroll in the clinical trial of Keytruda anyway.

“I wasn’t eating. I was on oxygen. I couldn’t walk,” he said. “When I went into the hospital at the end of May [2012], I didn’t think I was coming out.”

Gradually, though, Stutz started feeling better. Today, he’s no longer on oxygen and walks several miles every day.

“It’s the little things that make me happy now,” Stutz said. “I’m very appreciative that I get to get up in the morning, go into my backyard and see my garden. I’m able to be with my children and grandchildren, go on vacations with them. I was close to the end of the road, as far as you can get to the edge of the cliff, and I was pulled back by this treatment.”

Melanoma incidence rates have been increasing for at least 30 years. An estimated 76,100 new cases of melanoma will be diagnosed in the U.S. in 2014, and nearly 10,000 Americans will die from the disease this year. While melanoma accounts for less than 2 percent of all skin cancer cases, it is responsible for the vast majority of skin cancer deaths, according to the American Cancer Society.

In papers published in the American Journal of Public Health and the Bulletin of the History of Medicine, Aronowitz, professor and chair of Penn’s Department of History and Sociology of Science, characterizes the events then and screenings for prostate-specific antigen, or PSA, in more recent years as "part of one continuous story of how medical and lay people came to believe in the efficacy of population screening followed by aggressive treatment without solid supporting scientific evidence."

"This is a call to reflection about how we deal with medical knowledge production and medical technological innovation," Aronowitz said.

In 2012, the U.S. Preventive Services Task Force recommended that healthy men not be screened for prostate cancer with PSA tests. Millions of men, before and after this recommendation, have had screening PSA tests. If an individual’s PSA level is above a certain value, he may be counseled by a doctor to have repeated tests or a tissue biopsy to look for cancer cells. The biopsy is an invasive procedure, and can lead to additional procedures that escalate in their potential for detrimental effects. The recent Task Force decision states that the test has "very small potential benefit and significant potential harms."

Interested in how the PSA test and other prostate cancer screening measures rose in prominence, Aronowitz was researching the history of screening when he came upon a "largely forgotten" story.

In 1951, a young New York urologist began a study to determine whether biopsying the prostate glands of men without signs or symptoms, and then aggressively treating those individuals who had tissue diagnoses of cancer, could reduce deaths from prostate cancer.

Aronowitz details the history of the urologist’s trial, which lasted more than a decade and to which more than 1,200 homeless, alcoholic men from New York’s Bowery neighborhood were recruited. Participants traveled to Francis Delafield Hospital, where they received a physical exam, X-rays, and various invasive tests, including a prostate biopsy that involved the removal of a sizable amount of tissue. Men whose samples were found to contain cancerous cells then underwent aggressive treatment, typically including the removal of the prostate gland and testes and administration of a synthetic estrogen.

Though records are unclear, some men may have given a form of "informed consent" and some may have been aware that they were participating in research, Aronowitz found. But their vulnerable status, as homeless and alcoholic, calls into the question whether they were entering into the research with true free will and understanding, Aronowitz said. Given the state of clinical knowledge, he noted, these largely asymptomatic men clearly were also being exposed to undue risk.

Even though the prostate biopsy procedure today requires the removal of far less tissue and is less dangerous, Aronowitz draws a connection between the vulnerable Bowery population and the millions of men who each year are biopsied for cancer after recording a high level on a PSA screening test.

"Patients today are often not fully informed about risks and benefits of PSA screening," Aronowitz said. "More importantly, and like the Bowery men, many men today, and certainly men in the era before results from good clinical trials were available, have not been informed in the sense of knowing whether the test, and all that it may trigger, is worth it or not."

In the Bulletin of the History of Medicine paper, Aronowitz writes that society’s attitudes toward prostate cancer changed as a result of subsequent medical innovation that modified many aspects of the Bowery series but had similar goals. Where prostate cancer was once only diagnosed in very late stages when it was nearly always fatal, new screening tests enabled many diagnoses at much earlier stages, before patients displayed symptoms.

According to Aronowitz, however, the evidence we now have from randomized controlled trials either does not show that screening saves lives or shows a very small benefit that some men might experience does not outweigh the many known harms from cancer treatments, especially incontinence and impotence. Whether efficacious or not, the mass diffusion of screening and related practices occurred in an "evidence-free" way and transformed prostate cancer as a disease, Aronowitz argued.

"It’s not just costly or a little bit inconvenient to let innovation happen and deal with the ethical and clinical consequences later," he said. "We ended up with not just 1,200 but millions of men who were screened, and maybe a fifth of them go on to get more radical treatment.

"I think when you look back at the Bowery series, those involved were acting in good faith," he added. "So were many people who promoted PSA testing when they thought or continue to think it is only logical to use a test that detects cancer early enough for radical treatments to remove it from the body. But when a medical procedure will be offered at a population level with the potential to transform society and everything we think we know about the targeted disease, we ought to proceed with a very high level of caution, reflection, knowledge production and evaluation."